连接配体自激活蛋白酶激活受体4的结构机制
Structural mechanisms for self-activation of protease-activated receptor 4 by tethered ligand.
摘要(中文译文)
蛋白酶激活受体4（PAR4）在血栓形成过程中介导血小板活化，是抗血小板治疗的一个有前景的靶点。该受体在丝氨酸蛋白酶切割其N端时被激活，暴露出一个自身激活的系链配体。在此，我们报道了自身激活的PAR4与G异源三聚体复合物的冷冻电镜（cryo-EM）结构。系链配体结合于一个浅口袋，与跨膜束形成有限的相互作用，并呈现出与其他PAR亚型不同的侧向结合模式。它通过将构象重排传播至保守的微开关、触发螺旋8旋转来激活PAR4。G蛋白信号传导受到波浪钩浅层结合的独特调控，这种结合破坏了其与DRY基序的相互作用。分子对接表明，选择性激动剂PAR4-AP通过额外的疏水接触和稳定的盐桥增强激活，揭示了亚型选择性的决定因素。这些发现为PAR4信号传导提供了机制性见解，为发现靶向PAR4的抗血栓药物奠定了基础。
Abstract
Protease-activated receptor 4 (PAR4) mediates platelet activation during thrombosis and represents a promising target for antiplatelet therapies. This receptor is activated when serine proteases cleave its N terminus, exposing a self-activating tethered ligand. Here, we report the cryo-electron microscopy (cryo-EM) structure of self-activated PAR4 in complex with G heterotrimers. The tethered ligand binds a shallow pocket, forming limited interactions with the transmembrane bundle and adopting a lateral binding pattern distinct from other PAR subtypes. It activates PAR4 by propagating conformational rearrangements to conserved micro-switches, triggering helix 8 rotation. G signaling is uniquely modulated by shallow engagement of the wavy hook, which disrupts its interaction with the DRY motif. Molecular docking demonstrates that the selective agonist PAR4-AP enhances activation through additional hydrophobic contacts and a stabilizing salt bridge, revealing the determinants of subtype selectivity. These findings provide mechanistic insights into PAR4 signaling, laying a foundation for the discovery of PAR4-targeted antithrombotic drugs.
如何引用
AMA
Zhikang Xu, Jiacheng He, Zihan Zhou, Zhefan Yu, Yingnan Zhang, Anqi Chen, et al. Structural mechanisms for self-activation of protease-activated receptor 4 by tethered ligand.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117632.
APA
Zhikang Xu, Jiacheng He, Zihan Zhou, Zhefan Yu, Yingnan Zhang, Anqi Chen, et al (2026). Structural mechanisms for self-activation of protease-activated receptor 4 by tethered ligand.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117632
GB/T 7714
Zhikang Xu, Jiacheng He, Zihan Zhou, Zhefan Yu, Yingnan Zhang, Anqi Chen, et al. Structural mechanisms for self-activation of protease-activated receptor 4 by tethered ligand.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117632.
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